An increasing subgroup of patients with hypertrophic cardiomyopathy and refractory cardiac symptoms, despite treatment with standard medical therapies and surgery (whenever possible) has provided the impetus for investigating new forms of drug therapies. Amiodarone, a benzofurane compound, with potent antiarrhythmic properties, would appear to have a hemodynamic profile suitable in treating the physiologic abnormalities associated with hypertrophic cadiomyopathy. As such, 10 patients with hypertrophic cariomyopathy and refractory cardiac symptoms were treated with high dose oral amiodarone (800 to 1600 mg per day for 10 days) and was compared with no medications and previous best medical therapy (including calcium channel blockers and beta blockers). Therapeutic efficacy was assessed by exercise testing, ambulatory ECG monitoring, and semiquantitative symptom scores. Exercise duration increased greater than 100% from control valves in 70 of 10 patients. The improvement correlated poorly with changes in heart rate, other resting or exercise hemodynamic parameters, QT interval and amiodarone blood levels. Ventricular tachycardia during ambulatory monitoring was present in 6 patients on no medication, or best medical therapy, but was absent with amiodarone; nevertheless, one patient died suddenly 5 weeks after beginning amiodarone therapy. We conclude that high dose oral amiodarone, unrelated to its antiarrhythmic effects, improves exercise capacity and cardiac symptoms in many patients with hypertrophic cardiomyopathy and may be used as an alternative to current medical therapy in patients with refractory symptoms. However, the long term efficacy of amiodarone remains unknown.